Ara G, Kusumoto T, Korbut T T, Cullere-Luengo F, Teicher B A
Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
Cancer Res. 1994 Mar 15;54(6):1497-502.
Three human tumor cell lines made resistant to cis-diamminedichloroplatinum(II) (CDDP), SCC-25/CP, MCF-7/CP, and C13, are more sensitive to rhodamine-123 [tetrachloroplatinum(II)] [(PtCl4(Rh-123)2] than are the corresponding parental cell lines. The CDDP-resistant cells have higher intracellular concentrations of PtCl4(Rh-123)2 for the same exposure than do the parent cells. Each of the CDDP-resistant cell lines has an increased level of cytochrome c oxidase activity compared with the parent cell lines, indicating that the resistant cells have greater mitochondrial mass or activity than the parent cells. In fact, there was a linear correlation between the increase in cytochrome c oxidase activity and the increased sensitivity to PtCl4(Rh-123)2 in the CDDP-resistant lines. Exposure of the cells to each of the mitochondrial effectors, chloramphenicol, FCCP, oligomycin, or antimycin prior to and during exposure to CDDP or PtCl4(Rh-123)2 had variable effects on the cytotoxicity of the platinum complexes in the parental lines. However, there was a consistent decrease in the cytotoxicity of PtCl4(Rh-123)2 in the CDDP-resistant cells in the presence of the mitochondrial effectors such that, in some cases, the CDDP-resistant lines were now less responsive to PtCl4(Rh-123)2 than were the parent cell lines. These studies indicate that mitochondrial alterations may be an important component of CDDP resistance in these cell lines and that PtCl4(Rh-123)2 may represent a prototype platinum complex useful in the treatment of CDDP resistant tumors.
三种对顺二氯二氨铂（II）（CDDP）产生抗性的人肿瘤细胞系，即SCC - 25/CP、MCF - 7/CP和C13，比相应的亲本细胞系对罗丹明 - 123 [四氯铂（II）] [(PtCl4(Rh - 123)2] 更敏感。在相同暴露条件下，CDDP抗性细胞内PtCl4(Rh - 123)2的浓度高于亲本细胞。与亲本细胞系相比，每个CDDP抗性细胞系的细胞色素c氧化酶活性水平都有所提高，这表明抗性细胞比亲本细胞具有更大的线粒体质量或活性。事实上，在CDDP抗性细胞系中，细胞色素c氧化酶活性的增加与对PtCl4(Rh - 123)2敏感性的增加之间存在线性关系。在暴露于CDDP或PtCl4(Rh - 123)2之前及期间，将细胞暴露于每种线粒体效应物，即氯霉素、FCCP、寡霉素或抗霉素，对亲本细胞系中铂配合物的细胞毒性有不同影响。然而，在存在线粒体效应物的情况下，CDDP抗性细胞中PtCl4(Rh - 123)2的细胞毒性持续降低，以至于在某些情况下，CDDP抗性细胞系对PtCl4(Rh - 123)2的反应性现在比亲本细胞系更低。这些研究表明，线粒体改变可能是这些细胞系中CDDP抗性的一个重要组成部分，并且PtCl4(Rh - 123)2可能代表一种可用于治疗CDDP抗性肿瘤的铂配合物原型。
